Signal induced phosphorylation of IkappaBalpha, the inhibitor of NF-kappaB leads to its subsequent poly-ubiquitination and degradation by the ubiquitin proteasome pathway. This allows NF-kappaB to translocate into the nucleus of the cell and turn on a variety of stress response genes. The specific ubiquitin ligase of IkappaBalpha has been reported to be SCFBTrCP, which is a multiprotein complex. BTrCP is an F-Box protein that also contains a WD40 repeat motif. The F-box region of the protein binds Skp1, Cul1, and mediates the binding of an E2 (Ubch5c). The WD40 repeat motif binds phophorylated IkBa. A homolog of BTrCP is BTrCP2. The purpose of this grant is to determine whether BTrCP2 is a relevant IkB E3-ligase. And to understand the mechanism of E2 specificity associated with SCF ubiquitin ligase complexes.